This disclosure is directed to quaternary oxycodone, oxymorphone, hydrocodone and hydromorphone ammonium compounds described in general Formula I and to compositions and uses of said compounds for treating pain associated with a variety of chronic human disorders including for example neuropathic pain and pain associated with cancer, surgeries or injuries.
The compounds of the disclosure may be generically categorized within the class of compounds known as opioids. It is well known that opioid drugs target three types of endogenous opioid receptors (i.e., mu, delta and kappa receptors) in biological systems. Most opioids, such as morphine, are mu opioid agonists that are often used as analgesics for the treatment of severe pain due to their activation of mu opioid receptors in the brain and central nervous system (CNS). Opioid receptors are, however, not limited to the CNS, and have been found in other tissues throughout the body. A number of side effects of opioid drugs may be caused by activation of these peripheral receptors including nausea, vomiting and inhibition of normal propulsive gastrointestinal function resulting in side effects such as, for example, constipation, drowsiness, respiratory depression, changes in mood, and mental clouding without a resulting loss of consciousness. Thus, it is widely recognized that opioid treatment induced constipation is sometimes even more difficult to treat than the underlying pain. Towards this end, several ameliorating strategies have been developed which include, for example, the administration of opioid receptor antagonist such as for example, Naltrexon to patients for reversing opioid induced constipation. However, since central acting opioid receptor antagonists also reverse analgesia and precipitate opioid withdrawal symptoms, non CNS penetrant quaternary ammonium derivatives of opioid antagonist such as for example, Methyl Naltrexone have been developed and these derivatives have been shown to reverse peripheral side effects of opioids without inducing CNS mediated withdrawal symptoms or reversing analgesia. However, since use of opioid antagonists targets the amelioration of already manifested side effects, these treatment regimens add cost and burden to the treatment of pain. Accordingly there is a need for developing opioid derivatives that would exhibit reduced peripheral side-effects while maintaining central analgesic properties.
Moreover, prescription opioid use is also the subject of extensive “substance abuse” which is increasing and exacts a high toll on patients, physicians, and society. Nonmedical users of prescription pain relievers quadrupled from 1990 to 2000, with abuse of oxycodone and hydrocodone products particularly common. Extracting a societal toll, this prescription drug abuse is associated with higher rates of comorbidities and drug-related mortality.
Chronic pain and prescription opioid abuse are both highly prevalent. Chronic pain affects approximately 50 million Americans each year, and an additional 48 million Americans 12 years or older have used prescription drugs for nonmedical reasons in their lifetimes. Among the most potent analgesics available, opioids have a recognized role in the treatment of cancer- and non-cancer-related chronic pain conditions. Yet many physicians, concerned that their patients will become addicted, are reluctant to prescribe these agents, contributing to the widespread undertreatment of chronic pain.
One strategy for reducing the potential for abuse is development of tamper resistant opioid formulations designed to create barriers to manipulations of prescription drug formulations. Additionally, opioid formulations incorporating pharmacological strategies have also been designed to deter or resist misuse and abuse by making it difficult to achieve euphoria through opioid use. As pharmacologically proactive tools, these formulations use either pharmacodynamic or physical mechanisms to make opioids unattractive to individuals who abuse them, as well as present barriers to unintentional or deliberate misuse. Such formulations are currently available and have had mixed epidemiological results. New compounds and formulations that obviate the limitations of existing therapeutics are thus needed.
Pharmaceutical strategies have been developed as either agonist-antagonist or agonist-additional active ingredient combinations. Agonist-antagonist formulations can be considered pharmacodynamic strategies because they act to reduce reward at the receptor level. An example of such a strategy is Embeda™ (Pfizer™) which combines morphine with an antagonist such as naltrexone. If this formulation is ingested normally, the naltrexone remains latent; if it is crushed, the naltrexone is released and reduces the effects of the morphine Other agonist-antagonist combinations include Talwin™ containing pentazocine hydrochloride and naloxone hydrochloride equivalent; Valoron™, a combination of tilidine and naloxone; and Terngesic, a combination of buprenorphine and naloxone. These strategies cause, in some instances, opioid withdrawal symptoms.
Opioids with a reduced side effect and abuse potential are one of the most important unmet needs in the management of chronic pain and help physicians to better balance optimal analgesia with reduced risk of having to treat either opioid induced side effects or worry about prescription misuse and abuse.
Compounds of the present disclosure combine agonist/antagonist activity at opioid receptors in a single molecular entity and exploit (as principle of their pharmacological action) relative drug distribution/partitioning differences between agonist and quaternary ammonium antagonist in peripheral and central nervous system compartments, thereby reducing peripheral side effects associated with opioid receptor agonist use (such as GI effects, or respiratory depression and pruritis). In addition, by controlling the delivery of a centrally acting analgesic opioid through the rate of enzymatic conversion of a peripheral quaternary ammonium opioid antagonist, compounds of the present invention are abuse-resistant while maintaining analgesic properties of the parent opioid.
The invention relates to a compound of Formula I:
wherein R1 is CHR4O(C═O)OR5, CHR4O(C═O)R6, CHR4O(C═O)NR6R7, CHR4O(C═O)CHR8NR6R7, CHR4O(C═O)CHR8NH(COCHR8NH)nH, CHR4R9, CHR4O(C═O)CR5R6OR7, CHR4O(C═O)O(CH2)nNR5R6, CHR4O(C═O)O(CH2)nCO2R5, CHR4O(C═O)(CH2)nNR5R6, CHR4O(C═O)(CH2)nCO2R5,
R2 is H, OH, or O(C═O)CH3;R3 is H, CH3, or (C═O)CH3;R4 is H or optionally substituted alkyl; wherein said substituents are independently selected from the group OR3 and (C═O)OR5;R5 is optionally substituted alkyl, cycloalkyl, phenylalkyl, heteroalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein said substituents are independently (CH2)nCO2alkyl;R6 is H or R5;R7 is H or R5;R8 is H or R5;R9 is 4-isoxazoyl;wherein n is an integer from 1-12; andA is an anion selected from the group consisting of: Br−, Cl−, I−, R7CO2−, H2PO4−, NO3−, Etodolate, Mefenamate, Urosodeoxycholate and R6SO3.
Alkyl means unsubstituted and substituted, straight-chain and branched-chain alkyls having from 1 to 20 carbon atoms; alkyl may also contain one or multiple numbers of unsaturation including double and/or triple bonds; straight chain alkyl includes methyl, ethyl, propyl, butyl group, pentyl (to be also referred to as an amyl group) hexyl, decyl), branched chain alkyl group includes isopropyl, diethylmethyl, isobutyl, sec-butyl, t-butyl, isopentyl, t-pentyl, 2-ethylhexyl and the like; alkyl is also optionally substituted with 1 or more substituents independently selected from the group consisting of halo, hydroxy, alkoxy(alkoxy)x, hydroxyalkoxy(alkoxy)x, amino, monoalkylamino, dialkylamino, nitro, carboxyl, alkoxycarbonyl, and cyano, wherein x is an integer from 0 to 3 and the alkoxy contains from 1 to 5 carbon atoms.
Cycloalkyl means cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl; and said cyclic alkyl is optionally substituted with 1 or 2 substituents independently selected from the group consisting of halo, hydroxy, alkoxy(alkoxy)x, hydroxyalkoxy(alkoxy)x, amino, monoalkylamino, dialkylamino, nitro, carboxyl, alkoxycarbonyl, and cyano, wherein x is an integer from 0 to 3 and the alkoxy portion of the alkoxycarbonyl contains from 1 to 5 carbon atoms.
Phenylalkyl is selected from the group consisting of benzyl, phenylethyl and phenylpropyl; and the phenyl portion of the phenylalkyl is optionally substituted with 1 to 3 substituents independently selected from the group consisting of alkyl, hydroxy, alkoxy, halo, amino, monoalkylamino, dialkylamino, nitro, carboxyl, alkoxycarbonyl and cyano, wherein the phenyl portion of the phenylalkyl is unsubstituted or substituted.
Heteroalkyl means a straight or branched-chain having from one to 20 carbon atoms and one or more heteroatoms selected from nitrogen, oxygen, or sulphur, wherein the nitrogen and sulphur atoms may optionally be oxidized, i.e., in the form of an N-oxide or an S-oxide.
Heterocycloalkyl means a monocyclic or multicyclic ring system (which may be saturated or partially unsaturated), including fused and spiro rings, of about five to about 10 elements wherein one or more of the elements in the ring system is an element other than carbon and is selected from nitrogen, oxygen, silicon, or sulphur atoms.
Aryl means phenyl or napthyl wherein the phenyl or napthyl moiety is optionally substituted with 1 to 3 substituents independently selected from the group consisting of alkyl, hydroxy, alkoxy, halo, amino, monoalkylamino, dialkylamino, nitro, carboxyl, alkoxycarbonyl and cyano groups.
Heteroaryl means a five to about a 14-membered aromatic monocyclic or multicyclic hydrocarbon ring system, including fused and spiro rings, in which one or more of the elements in the ring system is an element other than carbon and is selected from nitrogen, oxygen, silicon, or sulphur and wherein an N atom may be in the form of an N-oxide.
Natural, synthetic, racemic, L-, or D-amino acid group as used herein refers to a substituent containing 1 to 20 amino acid. When two or more amino acids are linked together the group is known as a polypeptide. The polypeptide may be (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids. Polypeptides include the twenty naturally occurring amino acids. Specific polypeptides include one or more amino acids selected from glutamic acid, aspartic acid, arginine, asparagine, cysteine, lysine, threonine, or serine. Such peptides may be attached through the C-terminus or the N-terminus.
Selection of the particular amino acids will depend on the physical properties desired. For instance, properties such as bulk, lipophilicity, and hydrophilicity may be optimized according to selection parameters known to those skilled in the art.
Sugar or saccharide as used herein refers to a monosaccharide, a disaccharide, polysaccharide or sugar alcohol. Saccharide includes galactose, fructose, glucose, maltose, cellobiose, gentiobiose, melibiose, lactose, turanose, sophorose, trehalose, isotrehalose, isosaccharose, white sugar, mannitol, sorbitol, xylitol or inositol.
Compounds of Formula I exist in the form of quaternary ammonium cations ionically complexed with pharmaceutically acceptable anions derived from acids to form addition salts of the compounds of Formula I. The phrase “pharmaceutically acceptable salt(s)”, as used herein, unless otherwise indicated, includes salts of quaternary ammonium compounds of Formula I.
Suitable salts are formed from acids which form non-toxic salts and may include acids that are known to enhance the pharmacologic utility of opioids. Examples include the acetate, adipate, aspartate, benzoate, besylate, bicarbonate/carbonate, bisulphate/sulphate, borate, camsylate, chenodeoxycholate, citrate, cyclamate, edisylate, Etodolate, esylate, formate, fumarate, gluceptate, gluconate, glucuronate, hexafluorophosphate, hibenzate, hydrochloride/chloride, hydrobromide/bromide, hydroiodide/iodide, isethionate, lactate, malate, maleate, malonate, mefenamate, mesylate, methylsulphate, naphthylate, 2-napsylate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate/hydrogen phosphate/dihydrogen phosphate, pyroglutamate, salycilate, saccharate, stearate, succinate, tannate, tartrate, tosylate, trifluoroacetate, Ursodexoycholate and xinofoate salts. Suitable anions include Br−, Cl−, I−, R7CO2−, H2PO4−, NO3−, and R6SO3. Hemisalts may also be formed, for example, hemisulphate. For a review on suitable salts, see Handbook of Pharmaceutical Salts: Properties, Selection, and Use by Stahl and Wermuth (Wiley-VCH, 2002).
As used herein the term “Formula I” is defined to include all forms of the compounds of Formula I, including hydrates, solvates, isomers, crystalline and non-crystalline forms, isomorphs, polymorphs, and metabolites thereof.
The compounds of the present disclosure may exist in a continuum of solid states ranging from fully amorphous to fully crystalline. The term ‘amorphous’ refers to a state in which the material lacks long range order at the molecular level and, depending upon temperature, may exhibit the physical properties of a solid or a liquid. Typically such materials do not give distinctive X-ray diffraction patterns and, while exhibiting the properties of a solid, are more formally described as a liquid. Upon heating, a change from solid to liquid properties occurs which is characterized by a change of state, typically second order (‘glass transition’). The term ‘crystalline’ refers to a solid phase in which the material has a regular ordered internal structure at the molecular level and gives a distinctive X-ray diffraction pattern with defined peaks. Such materials when heated sufficiently will also exhibit the properties of a liquid, but the change from solid to liquid is characterized by a phase change, typically first order (Melting point′).
The compounds of the present disclosure may also exist in unsolvated and solvated forms. The term ‘solvate’ is used herein to describe a molecular complex comprising the compound according to the present disclosure and one or more pharmaceutically acceptable solvent molecules, for example, ethanol. The term ‘hydrate’ is employed when said solvent is water.
A currently accepted classification system for organic hydrates is one that defines isolated site, channel, or metal-ion coordinated hydrates—see Polymorphism in Pharmaceutical Solids by K. R. Morris (Ed. H. G. Brittain, Marcel Dekker, 1995). Isolated site hydrates are ones in which the water molecules are isolated from direct contact with each other by intervening organic molecules. In channel hydrates, the water molecules lie in lattice channels where they are next to other water molecules. In metal-ion coordinated hydrates, the water molecules are bonded to the metal ion.
When the solvent or water is tightly bound, the complex will have a well-defined stoichiometry independent of humidity. When, however, the solvent or water is weakly bound, as in channel solvates and hygroscopic compounds, the water/solvent content will be dependent on humidity and drying conditions. In such cases, non-stoichiometry will be the norm.
Also included within the aspects of the disclosed embodiments are multi-component complexes (other than salts and solvates) wherein the drug and at least one other component are present in stoichiometric or non-stoichiometric amounts. Complexes of this type include clathrates (drug-host inclusion complexes) and co-crystals. The latter are typically defined as crystalline complexes of neutral molecular constituents which are bound together through non-covalent interactions, but could also be a complex of a neutral molecule with a salt. Co-crystals may be prepared by melt crystallisation, by recrystallisation from solvents, or by physically grinding the components together—see Chem Commun, 17, 1889-1896, by O. Almarsson and M. J. Zaworotko (2004). For a general review of multi-component complexes, see J Pharm Sci, 64 (8), 1269-1288, by Haleblian (August 1975).
The compounds according to the disclosed embodiments may also exist in a mesomorphic state (mesophase or liquid crystal) when subjected to suitable conditions. The mesomorphic state is intermediate between the true crystalline state and the true liquid state (either melt or solution). Mesomorphism arising as the result of a change in temperature is described as ‘thermotropic’ and that resulting from the addition of a second component, such as water or another solvent, is described as ‘lyotropic’. Compounds that have the potential to form lyotropic mesophases are described as ‘amphiphilic’ and consist of molecules which possess an ionic (such as —COO−Na+, —COO−K+, or —SO3−Na+) or non-ionic (such as —N−N+(CH3)3) polar head group. For more information, see Crystals and the Polarizing Microscope by N. H. Hartshorne and A. Stuart, 4th Edition (Edward Arnold, 1970).
Hereinafter all references to compounds of Formula I include references to salts, solvates, multi-component complexes and liquid crystals thereof and to solvates, multi-component complexes and liquid crystals of salts thereof.
The compounds of the present disclosure include compounds of Formula I as hereinbefore defined, including all polymorphs and crystal habits thereof, and isomers thereof (including optical, geometric and tautomeric isomers) as hereinafter defined and isotopically-labeled compounds of Formula I.
The compounds of Formula I have asymmetric carbon and nitrogen atoms and exist as two or more stereoisomers. The bonds of the compounds of Formula I may be depicted herein using a solid line (—), a solid wedge (), or a dotted wedge (). The use of a solid line to depict bonds to asymmetric carbon atoms is meant to indicate that all possible stereoisomers (e.g. specific enantiomers, racemic mixtures, etc.) at that atom are included. The use of either a solid or dotted wedge to depict bonds to asymmetric atoms is meant to indicate that only the stereoisomer shown is meant to be included. It is possible that compounds of Formula I may contain more than one asymmetric atom. In those compounds, the use of a solid line to depict bonds to asymmetric atoms is meant to indicate that all possible stereoisomers are meant to be included. For example, unless stated otherwise, it is intended that the compounds of Formula I can exist as enantiomers and diastereomers or as racemates and mixtures thereof. The use of a solid line to depict bonds to one or more asymmetric atoms in a compound of Formula I and the use of a solid or dotted wedge to depict bonds to other asymmetric atoms in the same compound is meant to indicate that a mixture of diastereomers is present.
Stereoisomers of Formula I include cis and trans isomers, optical isomers such as R and S enantiomers, diastereomers, geometric isomers, rotational isomers, conformational isomers, and tautomers of the compounds of Formula I, including compounds exhibiting more than one type of isomerism; and mixtures thereof (such as racemates and diastereomeric pairs).
When any racemate crystallizes, crystals of two different types are possible. The first type is the racemic compound (true racemate) referred to above wherein one homogeneous form of crystal is produced containing both enantiomers in equimolar amounts. The second type is the racemic mixture or conglomerate wherein two forms of crystal are produced in equimolar amounts each comprising a single enantiomer.
The compounds of the Formula I may exhibit the phenomena of tautomerism and structural isomerism. For example, the compounds of Formula I may exist in several tautomeric forms, including the enol and imine form, and the keto and enamine form and geometric isomers and mixtures thereof. All such tautomeric forms are included within the scope of compounds of Formula I. Tautomers exist as mixtures of a tautomeric set in solution. In solid form, usually one tautomer predominates. Even though one tautomer may be described, the disclosed embodiments include all tautomers of the compounds of Formula I.
The present invention includes all pharmaceutically acceptable isotopically-labelled compounds of Formula I wherein one or more atoms are replaced by atoms having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number which predominates in nature.
Examples of isotopes suitable for inclusion in the compounds of the present disclosure include isotopes of hydrogen, such as 2H and 3H, carbon, such as 11C, 13C and 14C, chlorine, such as 36Cl, fluorine, such as 18F, iodine, such as 123I and 125I, nitrogen, such as 13N and 15N, oxygen, such as 15O, 17O and 18O, phosphorus, such as 32P, and sulphur, such as 35S.
Certain isotopically-labelled compounds of Formula I, for example, those incorporating a radioactive isotope, are useful in drug and/or substrate tissue distribution studies. The radioactive isotopes tritium, i.e. 3H, and carbon-14, i.e. 14C, are particularly useful for this purpose in view of their ease of incorporation and ready means of detection.
Substitution with heavier isotopes such as deuterium, i.e. 2H, may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements, and hence may be preferred in some circumstances.
Substitution with positron emitting isotopes, such as 11C, 18F, 15O and 13N, can be useful in Positron Emission Topography (PET) studies for examining substrate receptor occupancy.
Isotopically-labeled compounds of Formula I can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the accompanying Examples and Preparations using an appropriate isotopically-labeled reagent in place of the non-labeled reagent previously employed.
Another embodiment relates to compounds of Formula I, wherein the stereochemistry about the quaternary nitrogen center is in the “S” configuration.
Another embodiment relates to compounds of Formula I, wherein the stereochemistry about the quaternary nitrogen center is in the “R” configuration.
Compounds of Formula I of particular interest can be segregated according to established opioid skeletons (wherein R2 and R3 groups have been replaced) as described below:

Another embodiment of the present disclosure refers to compounds of Formula I wherein the R1 groups (taken together with the R4, R5 and R6 functionality) have the formulae:

Another embodiment relates to compounds of Formula I, wherein R1 is CHR4O(C═O)OR5.
Another embodiment relates to compounds of Formula I, wherein R1 is CHR4O(C═O)R6.
Another embodiment relates to compounds of Formula I, wherein R1 is CHR4O(C═O)NR6R7.
Another embodiment relates to compounds of Formula I, wherein R1 is CHR4O(C═O)CHR8NR6R7.
Another embodiment relates to compounds of Formula I, wherein R1 is CHR4O(C═O)CHR8NH(COCHR8NH)nH.
Another embodiment relates to compounds of Formula I, wherein R1 is CHR4R9.
Another embodiment relates to compounds of Formula I, wherein R1 is CHR4O(C═O)CR5R6OR7.
Another embodiment relates to compounds of Formula I, wherein R1 is CHR4O(C═O)O(CH2)nNR5R6.
Another embodiment relates to compounds of Formula I, wherein R1 is CHR4O(C═O)O(CH2)nCO2R5.
Another embodiment relates to compounds of Formula I, wherein R1 is CHR4O(C═O)(CH2)nNR5R6.
Another embodiment relates to compounds of Formula I, wherein R1 is CHR4O(C═O)(CH2)nCO2R5.
Another embodiment relates to compounds of Formula I, wherein R1 is
Another embodiment relates to compounds of Formula I, wherein R1 is

Another embodiment relates to compounds of Formula I, wherein R2 is H. Other embodiments relate to compounds of Formula I, wherein R2 is H and R1 is one of the aforesaid embodiments relating to R1.
Another embodiment relates to compounds of Formula I, wherein R2 is OH. Other embodiments relate to compounds of Formula I, wherein R2 is OH and R1 is one of the aforesaid embodiments relating to R1.
Another embodiment relates to compounds of Formula I, wherein R2 is O(C═O)CH3. Other embodiments relate to compounds of Formula I, wherein R2 is O(C═O)CH3 and R1 is one of the aforesaid embodiments relating to R1.
Another embodiment relates to compounds of Formula I, wherein R3 is H. Other embodiments relate to compounds of Formula I, wherein R3 is H and R1 is one of the aforesaid embodiments relating to R1. Other embodiments relate to compounds of Formula I, wherein R3 is H and R1 is one of the aforesaid embodiments relating to R1 and/or R2 is one of the aforesaid embodiments relating to R2.
Another embodiment relates to compounds of Formula I, wherein R3 is Methyl. Other embodiments relate to compounds of Formula I, wherein R3 is methyl and R1 is one of the aforesaid embodiments relating to R1. Other embodiments relate to compounds of Formula I, wherein R3 is methyl and R1 is one of the aforesaid embodiments relating to R1 and/or R2 is one of the aforesaid embodiments relating to R2.
Another embodiment relates to compounds of Formula I, wherein R3 is (C═O)CH3. Other embodiments relate to compounds of Formula I, wherein R3 is (C═O)CH3 and R1 is one of the aforesaid embodiments relating to R1. Other embodiments relate to compounds of Formula I, wherein R3 is (C═O)CH3 and R1 is one of the aforesaid embodiments relating to R1 and/or R2 is one of the aforesaid embodiments relating to R2.
Another embodiment relates to compounds of Formula I, wherein R4 is H. Other embodiments relate to compounds of Formula I, wherein R4 is H and R1 is one of the aforesaid embodiments relating to R1. Other embodiments relate to compounds of Formula I, wherein R4 is H and/or R1 is one of the aforesaid embodiments relating to R1 and/or R2 is one of the aforesaid embodiments relating to R2 and/or R3 is one of the aforesaid embodiments relating to R3.
Another embodiment relates to compounds of Formula I, wherein R4 is methyl, ethyl, isopropyl, t-butyl, diethylmethyl, or pentyl. Other embodiments relate to compounds of Formula I, wherein R4 is methyl, ethyl, isopropyl, t-butyl, diethylmethyl, or pentyl and R1 is one of the aforesaid embodiments relating to R1. Other embodiments relate to compounds of Formula I, wherein R4 is methyl, ethyl, isopropyl, t-butyl, diethylmethyl, or pentyl and/or R1 is one of the aforesaid embodiments relating to R1 and/or R2 is one of the aforesaid embodiments relating to R2 and/or R3 is one of the aforesaid embodiments relating to R3.
Another embodiment relates to compounds of Formula I, wherein R4 is alkyl optionally substituted with one or more substituents independently selected from the group OR3 and (C═O)OR5. Other embodiments relate to compounds of Formula I, wherein R4 is alkyl optionally substituted with one or more substituents independently selected from the group OR3 and (C═O)OR5 and R1 is one of the aforesaid embodiments relating to R1. Other embodiments relate to compounds of Formula I, wherein R4 is alkyl optionally substituted with one or more substituents independently selected from the group OR3 and (C═O)OR5 and/or R1 is one of the aforesaid embodiments relating to R1 and/or R2 is one of the aforesaid embodiments relating to R2 and/or R3 is one of the aforesaid embodiments relating to R3.
Another embodiment relates to compounds of Formula I, wherein R5 is alkyl selected from methyl, ethyl, isopropyl, n-butyl, or n-pentyl. Other embodiments relate to compounds of Formula I, wherein R5 is alkyl selected from methyl, ethyl, isopropyl, n-butyl, or n-pentyl and R1 is one of the aforesaid embodiments relating to R1. Other embodiments relate to compounds of Formula I, wherein R5 is alkyl selected from methyl, ethyl, isopropyl, n-butyl, or n-pentyl and/or R1 is one of the aforesaid embodiments relating to R1 and/or R2 is one of the aforesaid embodiments relating to R2 and/or R3 is one of the aforesaid embodiments relating to R3 and/or R4 is one of the aforesaid embodiments relating to R4.
Another embodiment relates to compounds of Formula I, wherein R5 is optionally substituted alkyl, wherein said substituent(s) is (CH2)nCO2alkyl; and wherein n is an integer from 1-12. Other embodiments relate to compounds of Formula I, wherein R5 is optionally substituted alkyl, wherein said substituent(s) is (CH2)nCO2alkyl; and wherein n is an integer from 1-12 and R1 is one of the aforesaid embodiments relating to R1. Other embodiments relate to compounds of Formula I, wherein R5 is optionally substituted alkyl, wherein said substituent(s) is (CH2)nCO2alkyl; and wherein n is an integer from 1-12 and/or R1 is one of the aforesaid embodiments relating to R1 and/or R2 is one of the aforesaid embodiments relating to R2 and/or R3 is one of the aforesaid embodiments relating to R3 and/or R4 is one of the aforesaid embodiments relating to R4.
Another embodiment relates to compounds of Formula I, wherein R5 is cyclohexyl. Other embodiments relate to compounds of Formula I, wherein R5 is cyclohexyl and R1 is one of the aforesaid embodiments relating to R1. Other embodiments relate to compounds of Formula I, R5 is cyclohexyl and/or R1 is one of the aforesaid embodiments relating to R1 and/or R2 is one of the aforesaid embodiments relating to R2 and/or R3 is one of the aforesaid embodiments relating to R3 and/or R4 is one of the aforesaid embodiments relating to R4.
Another embodiment relates to compounds of Formula I, wherein R5 is benzyl. Other embodiments relate to compounds of Formula I, wherein R5 is benzyl and R1 is one of the aforesaid embodiments relating to R1. Other embodiments relate to compounds of Formula I, R5 is benzyl and/or R1 is one of the aforesaid embodiments relating to R1 and/or R2 is one of the aforesaid embodiments relating to R2 and/or R3 is one of the aforesaid embodiments relating to R3 and/or R4 is one of the aforesaid embodiments relating to R4.
Another embodiment relates to compounds of Formula I, wherein R6 is H. Other embodiments relate to compounds of Formula I, wherein R6 is H and R1 is one of the aforesaid embodiments relating to R1. Other embodiments relate to compounds of Formula I, wherein R6 is H and/or R1 is one of the aforesaid embodiments relating to R1 and/or R2 is one of the aforesaid embodiments relating to R2 and/or R3 is one of the aforesaid embodiments relating to R3 and/or R4 is one of the aforesaid embodiments relating to R4.
Another embodiment relates to compounds of Formula I, wherein R6 is methyl. Other embodiments relate to compounds of Formula I, wherein R6 is methyl and R1 is one of the aforesaid embodiments relating to R1. Other embodiments relate to compounds of Formula I, R6 is methyl and/or R1 is one of the aforesaid embodiments relating to R1 and/or R2 is one of the aforesaid embodiments relating to R2 and/or R3 is one of the aforesaid embodiments relating to R3 and/or R4 is one of the aforesaid embodiments relating to R4.
Another embodiment relates to compounds of Formula I, wherein R6 is t-butyl. Other embodiments relate to compounds of Formula I, wherein R6 is t-butyl and R1 is one of the aforesaid embodiments relating to R1. Other embodiments relate to compounds of Formula I, wherein R6 is t-butyl and/or R1 is one of the aforesaid embodiments relating to R1 and/or R2 is one of the aforesaid embodiments relating to R2 and/or R3 is one of the aforesaid embodiments relating to R3 and/or R4 is one of the aforesaid embodiments relating to R4.
Another embodiment relates to compounds of Formula I, wherein R6 is i-propyl. Other embodiments relate to compounds of Formula I, wherein R6 is i-propyl and R1 is one of the aforesaid embodiments relating to R1. Other embodiments relate to compounds of Formula I, R6 is i-propyl and/or R1 is one of the aforesaid embodiments relating to R1 and/or R2 is one of the aforesaid embodiments relating to R2 and/or R3 is one of the aforesaid embodiments relating to R3 and/or R4 is one of the aforesaid embodiments relating to R4.
Another embodiment relates to compounds of Formula I, wherein R6 is cyclohexyl. Other embodiments relate to compounds of Formula I, wherein R6 is cyclohexyl and R1 is one of the aforesaid embodiments relating to R1. Other embodiments relate to compounds of Formula I, wherein R6 is cyclohexyl and/or R1 is one of the aforesaid embodiments relating to R1 and/or R2 is one of the aforesaid embodiments relating to R2 and/or R3 is one of the aforesaid embodiments relating to R3 and/or R4 is one of the aforesaid embodiments relating to R4.
Another embodiment relates to compounds of Formula I, wherein R6 is benzyl. Other embodiments relate to compounds of Formula I, wherein R6 is benzyl and R1 is one of the aforesaid embodiments relating to R1. Other embodiments relate to compounds of Formula I, R6 is benzyl and/or R1 is one of the aforesaid embodiments relating to R1 and/or R2 is one of the aforesaid embodiments relating to R2 and/or R3 is one of the aforesaid embodiments relating to R3 and/or R4 is one of the aforesaid embodiments relating to R4.
Another embodiment relates to compounds of Formula I, wherein R6 is phenyl. Other embodiments relate to compounds of Formula I, wherein R6 is phenyl and R1 is one of the aforesaid embodiments relating to R1. Other embodiments relate to compounds of Formula I, wherein R6 is phenyl and/or R1 is one of the aforesaid embodiments relating to R1 and/or R2 is one of the aforesaid embodiments relating to R2 and/or R3 is one of the aforesaid embodiments relating to R3 and/or R4 is one of the aforesaid embodiments relating to R4.
Another embodiment relates to compounds of Formula I, wherein R7 is H. Other embodiments relate to compounds of Formula I, wherein R7 is H and R1 is one of the aforesaid embodiments relating to R1. Other embodiments relate to compounds of Formula I, wherein R7 is H and/or R1 is one of the aforesaid embodiments relating to R1 and/or R2 is one of the aforesaid embodiments relating to R2 and/or R3 is one of the aforesaid embodiments relating to R3 and/or R4 is one of the aforesaid embodiments relating to R4.
Another embodiment relates to compounds of Formula I, wherein R7 is methyl. Other embodiments relate to compounds of Formula I, wherein R7 is methyl and R1 is one of the aforesaid embodiments relating to R1. Other embodiments relate to compounds of Formula I, wherein R7 is methyl and/or R1 is one of the aforesaid embodiments relating to R1 and/or R2 is one of the aforesaid embodiments relating to R2 and/or R3 is one of the aforesaid embodiments relating to R3 and/or R4 is one of the aforesaid embodiments relating to R4.
Another embodiment relates to compounds of Formula I, wherein R6 is H. Other embodiments relate to compounds of Formula I, wherein R8 is H and R1 is one of the aforesaid embodiments relating to R1. Other embodiments relate to compounds of Formula I, wherein R8 is H and/or R1 is one of the aforesaid embodiments relating to R1 and/or R2 is one of the aforesaid embodiments relating to R2 and/or R3 is one of the aforesaid embodiments relating to R3 and/or R4 is one of the aforesaid embodiments relating to R4.
Another embodiment relates to compounds of Formula I, wherein R8 is methyl. Other embodiments relate to compounds of Formula I, wherein R8 is methyl and R1 is one of the aforesaid embodiments relating to R1. Other embodiments relate to compounds of Formula I, wherein R8 is methyl and/or R1 is one of the aforesaid embodiments relating to R1 and/or R2 is one of the aforesaid embodiments relating to R2 and/or R3 is one of the aforesaid embodiments relating to R3 and/or R4 is one of the aforesaid embodiments relating to R4.
Another embodiment relates to compounds of Formula I, wherein R9 is 4-isoxazoyl. Other embodiments relate to said R9 4-isoxazoyl embodiments taken in combination with the R1, R2, R3, R4 and/or R5 embodiments described herein above.
Another embodiment relates to compounds of Formula I, wherein A is Br−. Other embodiments relate to said A as Br− embodiments taken in combination with the other R1, R2, R3, R4 and/or R5 embodiments described herein above.
Another embodiment relates to compounds of Formula I, wherein A is Cl−. Other embodiments relate to said A is Cl− embodiments taken in combination with the other R1, R2, R3, R4 and/or R5 embodiments described herein above.
Another embodiment relates to compounds of Formula I, wherein A is I−. Other embodiments relate to said A is I− embodiments taken in combination with the other R1, R2, R3, R4 and/or R5 embodiments described herein above.
Another embodiment relates to compounds of Formula I, wherein A is R7CO2−, more specifically lactate, acetate, tartrate, and valerate. Other embodiments relate to said A is R7CO2− embodiments taken in combination with the other R1, R2, R3, R4 and/or R5 embodiments. described herein above.
Another embodiment relates to compounds of Formula I, wherein A is H2PO4−. Other embodiments relate to said A as H2PO4− embodiments taken in combination with the other R1, R2, R3, R4 and/or R5 embodiments described herein above.
Another embodiment relates to compounds of Formula I, wherein A is NO3−. Other embodiments relate to said A as NO3− embodiments taken in combination with the other R1, R2, R3, R4 and/or R5 embodiments described herein above.
Another embodiment relates to compounds of Formula I, wherein A is R6SO3. Other embodiments relate to said A as R6SO3 embodiments taken in combination with the other R1, R2, R3, R4 and/or R5 embodiments described herein above.
Another embodiment relates to compounds of Formula I, wherein A is Ursodeoxycholate. Other embodiments relate to said A as Ursodeoxycholate embodiments taken in combination with the other R1, R2, R3, R4 and/or R5 embodiments described herein above.
Another embodiment relates to compounds of Formula I, wherein A is Etodolate. Other embodiments relate to said A as Etodolate embodiments taken in combination with the other R1, R2, R3, R4 and/or R5 embodiments described herein above.
Another embodiment relates to compounds of Formula I, wherein A is Mefanamate. Other embodiments relate to said A as Mefanamate embodiments taken in combination with the other R1, R2, R3, R4 and/or R5 embodiments described herein above.
Another embodiment of the invention relates to the following specific compounds of the invention:

The compounds of Formula I (and the other embodiments above) are useful in the treatment of pain, particularly neuropathic, nociceptive and inflammatory pain.
Another embodiment relates to a method of treating acute or chronic pain comprising administering to a patient an effective amount of a compound of Formula I.
The aspects of the disclosed embodiments also relate to compositions comprising a compound of Formula I. Accordingly one embodiment relates to a pharmaceutical composition comprising a pharmaceutically effective amount of a compound of Formula I, a pharmaceutically acceptable carrier and, optionally, at least one additional medicinal or pharmaceutical agent.
Another embodiment relates to a composition of any of the aforesaid embodiments of compounds of Formula I wherein said composition is in tablet, capsule, oral solution, or oral suspension dosage form.
Another embodiment relates to a composition of a compound of Formula I wherein said composition is in tablet or capsule dosage form.
Another embodiment relates to an oral pharmaceutical preparation containing a therapeutically effective amount of a compound of Formula I for once daily administration.
Another embodiment relates to a sustained release composition containing a compound of Formula I.
In yet further embodiments, the pharmaceutical composition in addition to the compound of Formula I may further include a non-opioid drug. Such non-opioid drugs would preferably provide additional analgesia, and include, for example, aspirin; acetaminophen; non-steroidal anti-inflammatory drugs (“NSAIDS”), e.g., ibuprofen, ketoprofen, etc.; N-methyl-D-aspartate (NMDA) receptor antagonists, e.g., a morphinan such as dextromethorphan or dextrorphan, or ketamine; cyclooxygenase-II inhibitors (“COX-II inhibitors”); and/or glycine receptor antagonists.
Suitable non-steroidal anti-inflammatory agents, include ibuprofen, diclofenac, naproxen, benoxaprofen, flurbiprofen, fenoprofen, flubufen, ketoprofen, indoprofen, piroprofen, carprofen, oxaprozin, pramoprofen, muroprofen, trioxaprofen, suprofen, aminoprofen, tiaprofenic acid, fluprofen, bucloxic acid, indomethacin, sulindac, tolmetin, zomepirac, tiopinac, zidometacin, acemetacin, fentiazac, clidanac, oxpinac, mefenamic acid, meclofenamic acid, flufenamic acid, niflumic acid, tolfenamic acid, diflurisal, flufenisal, piroxicam, sudoxicam, isoxicam, pharmaceutically acceptable salts thereof, mixtures thereof, and the like. Useful dosages of these drugs are well known to those skilled in the art.
N-methyl-D-aspartate (NMDA) receptor antagonists are well known in the art, and encompass, for example, morphinans such as dextromethorphan or dextrorphan, ketamine, or pharmaceutically acceptable salts thereof. For purposes of the present disclosure, the term “NMDA antagonist” is also deemed to encompass drugs that at least partially inhibit a major intracellular consequence of NMDA-receptor activation, e.g. a ganglioside such as GM.sub.1 or GT.sub.1b, a phenothiazine such as trifluoperazine or a naphthalenesulfonamide such as N-(6-aminothexyl)-5-chloro-1-naphthalenesulfonamide. These drugs are stated to inhibit the development of tolerance to and/or dependence on addictive drugs, e.g., narcotic analgesics such as morphine, codeine, etc. in U.S. Pat. Nos. 5,321,012 and 5,556,838 (both to Mayer, et al.), and to treat chronic pain in U.S. Pat. No. 5,502,058 (Mayer, et al.). The NMDA antagonist may be included alone, or in combination with a local anesthetic such as lidocaine, as described in these Mayer, et al. patents.
The treatment of chronic pain via the use of glycine receptor antagonists and the identification of such drugs is described in U.S. Pat. No. 5,514,680 (Weber, et al.).
COX-2 inhibitors have been reported in the art and many chemical structures are known to produce inhibition of cyclooxygenase-2. COX-2 inhibitors are described, for example, in U.S. Pat. Nos. 5,616,601; 5,604,260; 5,593,994; 5,550,142; 5,536,752; 5,521,213; 5,475,995; 5,639,780; 5,604,253; 5,552,422; 5,510,368; 5,436,265; 5,409,944; and 5,130,311. Certain preferred COX-2 inhibitors include celecoxib, flosulide, meloxicam, 6-methoxy-2 naphthylacetic acid (6-MNA), nabumetone (prodrug for 6-MNA), nimesulide, or combinations thereof. Dosage levels of COX-2 inhibitor on the order of from about 0.005 mg to about 140 mg per kilogram of body weight per day are therapeutically effective in combination with the compounds of Formula I. Alternatively, about 0.25 mg to about 7 g per patient per day of a COX-2 inhibitor is administered in a combination.
In yet further embodiments, a non-opioid drug can be included which provides a desired effect other than analgesia, e.g., antitussive, expectorant, decongestant, antihistamine drugs, local anesthetics, and the like.
The pharmaceutically acceptable carrier may comprise any conventional pharmaceutical carrier or excipient. Suitable pharmaceutical carriers include inert diluents or fillers, water and various organic solvents (such as hydrates and solvates). The pharmaceutical compositions may, if desired, contain additional ingredients such as flavorings, binders, excipients and the like. Thus for oral administration, tablets containing various excipients, such as citric acid may be employed together with various disintegrants such as starch, alginic acid and certain complex silicates and with binding agents such as sucrose, gelatin and acacia. Additionally, lubricating agents such as magnesium stearate, sodium lauryl sulfate and talc are often useful for tableting purposes. Solid compositions of a similar type may also be employed in soft and hard filled gelatin capsules. Non-limiting examples of materials, therefore, include lactose or milk sugar and high molecular weight polyethylene glycols.
The pharmaceutical composition may, for example, be in a form suitable for oral administration as a tablet, capsule, pill, powder, sustained release formulations, solution suspension, for parenteral injection as a sterile solution, suspension or emulsion, for topical administration as an ointment or cream or for rectal administration as a suppository.
Physiological pain is an important protective mechanism designed to warn of danger from potentially injurious stimuli from the external environment. The system operates through a specific set of primary sensory neurons and is activated by noxious stimuli via peripheral transducing mechanisms (see Millan, 1999, Prog. Neurobiol., 57, 1-164 for a review). These sensory fibers are known as nociceptors and are characteristically small diameter axons with slow conduction velocities. Nociceptors encode the intensity, duration and quality of noxious stimulus and by virtue of their topographically organized projection to the spinal cord, the location of the stimulus. The nociceptors are found on nociceptive nerve fibers of which there are two main types, A-delta fibres (myelinated) and C fibres (non-myelinated). The activity generated by nociceptor input is transferred, after complex processing in the dorsal horn, either directly, or via brain stem relay nuclei, to the ventrobasal thalamus and then on to the cortex, where the sensation of pain is generated.
Pain may generally be classified as acute or chronic. Acute pain begins suddenly and is short-lived (usually twelve weeks or less). It is usually associated with a specific cause such as a specific injury and is often sharp and severe. It is the kind of pain that can occur after specific injuries resulting from surgery, dental work, a strain or a sprain. Acute pain does not generally result in any persistent psychological response. In contrast, chronic pain is long-term pain, typically persisting for more than three months and leading to significant psychological and emotional problems. Common examples of chronic pain are neuropathic pain (e.g. painful diabetic neuropathy, post herpetic neuralgia), carpal tunnel syndrome, back pain, headache, cancer pain, arthritic pain and chronic post-surgical pain.
When a substantial injury occurs to body tissue, via disease or trauma, the characteristics of nociceptor activation are altered and there is sensitization in the periphery, locally around the injury and centrally where the nociceptors terminate. These effects lead to a heightened sensation of pain. In acute pain these mechanisms can be useful, in promoting protective behaviors which may better enable repair processes to take place. The normal expectation would be that sensitivity returns to normal once the injury has healed. However, in many chronic pain states, the hypersensitivity far outlasts the healing process and is often due to nervous system injury. This injury often leads to abnormalities in sensory nerve fibers associated with maladaptation and aberrant activity (Woolf & Salter, 2000, Science, 288, 1765-1768).
Clinical pain is present when discomfort and abnormal sensitivity feature among the patient's symptoms. Patients tend to be quite heterogeneous and may present with various pain symptoms. Such symptoms include: 1) spontaneous pain which may be dull, burning, or stabbing; 2) exaggerated pain responses to noxious stimuli (hyperalgesia); and 3) pain produced by normally innocuous stimuli (allodynia—Meyer et al., 1994, Textbook of Pain, 13-44). Although patients suffering from various forms of acute and chronic pain may have similar symptoms, the underlying mechanisms may be different and may, therefore, require different treatment strategies. Pain can also therefore be divided into a number of different subtypes according to differing pathophysiology, including nociceptive, inflammatory and neuropathic pain.
Nociceptive pain is induced by tissue injury or by intense stimuli with the potential to cause injury. Pain afferents are activated by transduction of stimuli by nociceptors at the site of injury and activate neurons in the spinal cord at the level of their termination. This is then relayed up the spinal tracts to the brain where pain is perceived (Meyer et al., 1994, Textbook of Pain, 13-44). The activation of nociceptors activates two types of afferent nerve fibers. Myelinated A-delta fibers transmit rapidly and are responsible for sharp and stabbing pain sensations, whilst unmyelinated C fibers transmit at a slower rate and convey a dull or aching pain. Moderate to severe acute nociceptive pain is a prominent feature of pain from central nervous system trauma, strains/sprains, burns, myocardial infarction and acute pancreatitis, post-operative pain (pain following any type of surgical procedure), posttraumatic pain, renal colic, cancer pain and back pain. Cancer pain may be chronic pain such as tumor related pain (e.g. bone pain, headache, facial pain or visceral pain) or pain associated with cancer therapy (e.g. post chemotherapy syndrome, chronic postsurgical pain syndrome or post radiation syndrome). Cancer pain may also occur in response to chemotherapy, immunotherapy, hormonal therapy or radiotherapy. Back pain may be due to herniated or ruptured intervertebral discs or abnormalities of the lumber facet joints, sacroiliac joints, paraspinal muscles or the posterior longitudinal ligament. Back pain may resolve naturally but in some patients, where it lasts over 12 weeks, it becomes a chronic condition which can be particularly debilitating.
Neuropathic pain is currently defined as pain initiated or caused by a primary lesion or dysfunction in the nervous system. Nerve damage can be caused by trauma and disease and thus the term ‘neuropathic pain’ encompasses many disorders with diverse etiologies. These include, but are not limited to, peripheral neuropathy, diabetic neuropathy, post herpetic neuralgia, trigeminal neuralgia, back pain, cancer neuropathy, HIV neuropathy, phantom limb pain, carpal tunnel syndrome, central post-stroke pain and pain associated with chronic alcoholism, hypothyroidism, uremia, multiple sclerosis, spinal cord injury, Parkinson's disease, epilepsy and vitamin deficiency. Neuropathic pain is pathological as it has no protective role. It is often present well after the original cause has dissipated, commonly lasting for years, significantly decreasing a patient's quality of life (Woolf and Mannion, 1999, Lancet, 353, 1959-1964). The symptoms of neuropathic pain are difficult to treat, as they are often heterogeneous even between patients with the same disease (Woolf & Decosterd, 1999, Pain Supp., 6, S141-S147; Woolf and Mannion, 1999, Lancet, 353, 1959-1964). They include spontaneous pain, which can be continuous, and paroxysmal or abnormal evoked pain, such as hyperalgesia (increased sensitivity to a noxious stimulus) and allodynia (sensitivity to a normally innocuous stimulus).
The inflammatory process is a complex series of biochemical and cellular events, activated in response to tissue injury or the presence of foreign substances, which results in swelling and pain (Levine and Taiwo, 1994, Textbook of Pain, 45-56). Arthritic pain is the most common inflammatory pain. Rheumatoid disease is one of the commonest chronic inflammatory conditions in developed countries and rheumatoid arthritis is a common cause of disability. The exact etiology of rheumatoid arthritis is unknown, but current hypotheses suggest that both genetic and microbiological factors may be important (Grennan & Jayson, 1994, Textbook of Pain, 397-407). It has been estimated that almost 16 million Americans have symptomatic osteoarthritis (OA) or degenerative joint disease, most of whom are over 60 years of age, and this is expected to increase to 40 million as the age of the population increases, making this a public health problem of enormous magnitude (Houge & Mersfelder, 2002, Ann Pharmacother., 36, 679-686; McCarthy et al., 1994, Textbook of Pain, 387-395). Most patients with osteoarthritis seek medical attention because of the associated pain. Arthritis has a significant impact on psychosocial and physical function and is known to be the leading cause of disability in later life. Ankylosing spondylitis is also a rheumatic disease that causes arthritis of the spine and sacroiliac joints. It varies from intermittent episodes of back pain that occur throughout life to a severe chronic disease that attacks the spine, peripheral joints and other body organs.
Another type of inflammatory pain is visceral pain which includes pain associated with inflammatory bowel disease (IBD). Visceral pain is pain associated with the viscera, which encompass the organs of the abdominal cavity. These organs include the sex organs, spleen and part of the digestive system. Pain associated with the viscera can be divided into digestive visceral pain and non-digestive visceral pain. Commonly encountered gastrointestinal (GI) disorders that cause pain include functional bowel disorder (FBD) and inflammatory bowel disease (IBD). These GI disorders include a wide range of disease states that are currently only moderately controlled, including, in respect of FBD, gastro-esophageal reflux, dyspepsia, irritable bowel syndrome (IBS) and functional abdominal pain syndrome (FAPS), and, in respect of IBD, Crohn's disease, ileitis and ulcerative colitis, all of which regularly produce visceral pain. Other types of visceral pain include the pain associated with dysmenorrhea, cystitis and pancreatitis and pelvic pain.
It should be noted that some types of pain have multiple etiologies and thus can be classified in more than one area, e.g. back pain and cancer pain have both nociceptive and neuropathic components.
Other types of pain include: pain resulting from muscular-skeletal disorders, including myalgia, fibromyalgia, spondylitis, sero-negative (non-rheumatoid) arthropathies, non-articular rheumatism, dystrophinopathy, glycogenolysis, polymyositis and pyomyositis; heart and vascular pain, including pain caused by angina, myocardical infarction, mitral stenosis, pericarditis, Raynaud's phenomenon, scleredoma and skeletal muscle ischemia; head pain, such as migraine (including migraine with aura and migraine without aura), cluster headache, tension-type headache mixed headache and headache associated with vascular disorders; erythermalgia; and orofacial pain, including dental pain, otic pain, burning mouth syndrome and temporomandibular myofascial pain.
The term “treating”, as used herein, unless otherwise indicated, means reversing, alleviating, inhibiting the progress of, or preventing the disorder or condition to which such term applies, or one or more symptoms of such disorder or condition. The term “treatment”, as used herein, unless otherwise indicated, refers to the act of treating as “treating” is defined immediately above. The term “treating” also includes adjuvant and neo-adjuvant treatment of a subject.
Administration of the compounds of Formula I may be effected by any method that enables delivery of the compounds to the site of action. These methods include oral routes, intraduodenal routes, parenteral injection (including intravenous, subcutaneous, intramuscular, intravascular or infusion), topical, and rectal administration.
The aspects of the disclosed embodiments also relate to altering the pharmacokinetic and pharmacological properties of opioids, particularly oxycodone, oxymorphone, hydrocodone and hydromorphone, through quaternization of the bicyclic tertiary amine embedded in the opioid structure. It is well known to those skilled in the art that quaternization can change the rate and extent of absorption, metabolism, distribution, and elimination of adrug. Moreover, preferred quaternary ammonium compounds of the present disclosure possess opioid antagonist activity. Furthermore, the quaternary ammonium compounds of the disclosure, when ingested or administered to a patient by any other means, are converted to free base opioid possessing agonist activity at opioid receptors. Thus, these compounds inherently possess both antagonist and agonist properties. When the quaternary ammonium compound is first orally administered it may bind to opioid receptors. More specifically, if a quaternary ammonium compound of the disclosure is orally ingested, the compound upon reaching the intestinal tract binds to the mu or delta opioid receptor acting as an antagonist. Simultaneously, quaternary ammonium opioid compound is subject to the action of intestinal metabolic action and uptake and further metabolism by intestinal wall transmission processes. These processes are responsible for converting the quaternary ammonium opioid into the tertiary amine parent compound (i.e. oxycodone, oxymorphone and hydromorphone). Although the opioid is now free to act in the intestinal tract as an agonist the receptors have already been blocked by prior saturation with the antagonistic quaternary compound. This localized inactivation of opioid receptors reduces local side effects such as constipation, a major side effect of agonists. When administered at a normal therapeutic dose the bioavailablility (the time-versus-concentration curve; area under the curve; AUC) of the opioid may be similar to that observed with slow or extended release formulations of the parent free base opioid compound. However, since the uptake (systemic bioavailability) of the quaternary ammonium opioid derivative into the circulation is generally much lower when compared with the uptake of the parent opioid compounds, this differential uptake property causes a relative decline of the parent opioid agonist concentration in intestinal compartments and maintains the potential of the antagonist to reduce agonist induced constipation. In contrast, the parent opioid agonist derived from the quaternary ammonium precursor through the action of metabolic enzymes is readily taken up into the circulation, enters the central nervous system where it exerts its analgesic activity. Moreover, the quaternary ammonium antagonist is restricted from crossing the blood brain barrier and thus has negligible penetration into the central nervous system. Furthermore, since means for generating euphoria aim at very rapid delivery of relatively large amounts of an opioid into the central nervous system; compounds embraced in general formula 1 are abuse resistant because enzymes control the amounts of opioid available for CNS uptake and the speed of release from a quaternary ammonium precursor cannot be altered even if compounds are taken above doses intended in the prescription or in deviation of the recommended route of administration. Likewise, the active principal in opioid abuse cannot be easily obtained from quaternary ammonium precursors adding a second barrier to drug abuse. This in turn diminishes the abuse potential, whether unintended or intentionally sought.
Persons that abuse opioids such as hydrocodone or oxycodone commonly seek to increase their euphoria by snorting or injecting the drugs. These routes of administration increase the rate and extent of drug absorption and provide a faster, nearly instantaneous, effect. This increases the amount of drug that reaches the central nervous system where it has its effect. In a particular aspect of the disclosed embodiments, the bioavailability of the covalently modified opioid is substantially decreased by the intranasal and intravenous routes as compared to the parent opioid compound. Thus the illicit practice of snorting and shooting the drug loses its advantage.
Dosage regimens may be adjusted to provide the optimum desired response. For example, a single bolus may be administered, several divided doses may be administered over time or the dose may be proportionally reduced or increased as indicated by the exigencies of the therapeutic situation. It is especially advantageous to formulate parenteral compositions in dosage unit form for ease of administration and uniformity of dosage. Dosage unit form, as used herein, refers to physically discrete units suited as unitary dosages for the mammalian subjects to be treated; each unit containing a predetermined quantity of active compound calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier.
Thus, the skilled artisan would appreciate, based upon the disclosure provided herein, that the dose and dosing regimen is adjusted in accordance with methods well-known in the therapeutic arts. That is, the maximum tolerable dose can be readily established, and the effective amount providing a detectable therapeutic benefit to a patient may also be determined, as can the temporal requirements for administering each agent to provide a detectable therapeutic benefit to the patient. Accordingly, while certain dose and administration regimens are exemplified herein, these examples in no way limit the dose and administration regimen that may be provided to a patient in practicing the aspects of the disclosed embodiments.
It is to be noted that dosage values may vary with the type and severity of the condition to be alleviated, and may include single or multiple doses. It is to be further understood that for any particular subject, specific dosage regimens should be adjusted over time according to the individual need and the professional judgment of the person administering or supervising the administration of the compositions, and that dosage ranges set forth herein are exemplary only and are not intended to limit the scope or practice of the claimed composition. For example, doses may be adjusted based on pharmacokinetic or pharmacodynamic parameters, which may include clinical effects such as toxic effects and/or laboratory values. Thus, the aspects of the disclosed embodiments encompass intra-patient dose-escalation as determined by the skilled artisan. Determining appropriate dosages and regimens for administration of the active agent are well-known in the relevant art and would be understood to be encompassed by the skilled artisan once provided the teachings disclosed herein.
The amount of the compound of Formula I administered will be dependent on the subject being treated, the severity of the disorder or condition, the rate of administration, the disposition of the compound and the discretion of the prescribing physician. However, an effective dosage is in the range of about 0.001 to about 100 mg per kg body weight per day, preferably about 1 to about 35 mg/kg/day, in single or divided doses. For a 70 kg human, this would amount to about 0.05 to about 7 g/day, preferably about 0.1 to about 2.5 g/day. In some instances, dosage levels below the lower limit of the aforesaid range may be more than adequate, while in other cases still larger doses may be employed without causing any harmful side effect, provided that such larger doses are first divided into several small doses for administration throughout the day.
As used herein, the term “combination therapy” refers to the administration of a compound of Formula I together with an at least one additional pharmaceutical or medicinal agent, either sequentially or simultaneously.
The aspects of the disclosed embodiments include the use of a combination of a compound as provided in Formula I and one or more additional pharmaceutically active agent(s). If a combination of active agents is administered, then they may be administered sequentially or simultaneously, in separate dosage forms or combined in a single dosage form. Accordingly, the present disclosure also includes pharmaceutical compositions comprising an amount of: (a) a first agent comprising a compound of Formula I; (b) a second pharmaceutically active agent; and (c) a pharmaceutically acceptable carrier, vehicle or diluent.
Various pharmaceutically active agents may be selected for use in conjunction with the compounds of Formula I, depending on the disease, disorder, or condition to be treated.